Fracture risk assessment is integral to the diagnosis and management of osteoporosis, a devastating clinical problem of which over 40 million Americans are at risk. Due to limitations in areal BMD measures obtained from 2D DXA scans - which is the current clinical standard for diagnosis of osteoporosis - it has recently become clear that those at greatest risk of osteoporotic fracture need to be better identified. A 3D biomechanics-based technique, which we term Biomechanical Computed Tomography (BCT), addresses this need through a combination of engineering finite element analysis, 3D quantitative computed tomography (QCT), and bone biomechanics. The main outcome parameter of BCT is an estimate of the biomechanical risk of a bone fracture that accounts for such factors as the patient's 3D bone geometry and distribution of bone density, body-weight, height, trochanteric soft tissue thickness (for hip fractures), and age, thereby shifting focus to the overall structure and mechanics of bone rather than simply density. BCT has already demonstrated its ability to produce accurate, noninvasive measures of bone strength on cadavers, and is now ready for clinical development. The long-term objective of O. N. Diagnostics is to offer BCT as a clinical alternative to DXA. Toward that end, the overall goal of the proposed project is to test the scientific hypothesis that, compared to areal BMD, BCT is a superior predictor of clinical fracture risk at the spine and hip for both women and men. To do this, we will analyze two unique clinical cohorts in a two-stage approach to provide a rigorous and general clinical validation of the BCT technique. We will first apply BCT to analysis of the "Mayo cohort", an age-stratified random sample of approximately 700 community-dwelling men and women from Rochester MN for which fracture incidence is well characterized. After calibrating the BCT outcomes against this sample, we will characterize normative values (as a function of age) and fracture threshold values of the BCT outcomes, essential information for eventual clinical interpretation of a BCT medical report. Having calibrated the BCT outcomes on the Mayo cohort, we will then prospectively test the ability of BCT - without any further calibration - to predict incident fractures using the "AGES cohort" and proceed to test our Hypothesis that BCT is a better predictor of fracture than areal BMD. The AGES cohort of over 5500 residents from Reykjavik, Iceland, is unique since both hip and spine clinical fracture data are available for both men and women (as are the QCT scans) in sufficient numbers for rigorous statistical testing. Phase I of the project will focus on analysis of hip fracture incidence for women in the Mayo cohort and is expected to provide evidence of the superior ability of BCT over areal BMD in predicting the age-related increases in hip fracture incidence. Because this overall project may significantly improve the ability to identify those women and men at highest risk of osteoporotic fracture, it represents a key step in establishing BCT as a clinical alternative to DXA, and an important advancement in the preventative care and treatment of such fractures. [unreadable] This project will provide clinical validation to Biomechanical Computed Tomography, a promising clinical alternative to DXA for the diagnosis of osteoporosis. Successful clinical implementation of BCT has the potential to greatly improve non-invasive assessment of fracture risk, which would represent an important advance in the preventative care and treatment of osteoporosis. [unreadable] [unreadable] [unreadable] [unreadable]